PROJECT SUMMARY Advanced aging is the primary factor associated with an adult diagnosis of glioblastoma (GBM) with wild-type isocitrate dehydrogenase; constituting 90% of all GBM diagnoses and the most commonly aggressive primary brain tumor of the central nervous system (CNS). Adult GBM is associated with a median overall survival (OS) of 15 months and the prognosis significantly decreases with progressive aging. Since standard of care treatment including maximal surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ) inevitably leads to a 100% mortality rate, immunotherapy has been proposed as a potential future approach for GBM patients, based on its success in treating patients with other aggressive cancers. However, in contrast to the growing list of end-stage malignancies that respond beneficially to anti-PD-1 mAb and/or anti-CTLA-4 mAb treatment, patients diagnosed with GBM and treated with immunotherapy have thus far failed to demonstrate an improved survival among all phase III clinical trials to-date. The goal of my K02 application is therefore to define the advanced aging-dependent increase of immunosuppressive factors that inhibit the anti-GBM immune response, as well as to understand how aging-increased immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO1) non- canonically decreases the response to immunotherapy. Previous work from my group discovered that, advanced aging increases immunosuppressive IDO1 gene expression in the normal human and mouse brain. We also showed that, immunotherapeutic treatment combining radiotherapy (RT) with anti-PD-1 mAb and an IDO1 enzyme inhibitor, leads to a long-term (?150 days) survival benefit in 6-12 week old immunocompetent mice with intracranial GBM. Strikingly, the treatment was made significantly less effective at improving survival in older subjects when engrafted the exact same tumor cells. My working hypothesis is that, advanced aging increases immunosuppression in the CNS that limits immunosurveillance mechanisms responsible for preventing GBM cell outgrowth and suppressing immune system responsiveness to immunotherapy. The protected time during K02 support will allow for comprehensive aging-specific training, high-level interactions with an expert committee of scientists that have broad experience exploring the interactions between aging, cancer, and/or the immune response, and will provide me with the necessary time to develop competitive R01 applications to support a future program of research focused on aging in the setting of GBM; a disease that remains incurable.